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ABSTRACT
Multiple Myeloma (MM) is a neoplasm with a annual incidence of 3 new cases per 100.000, with a mean age of onset of 70 years, with a prevalence among males. Prognosis is variable and is ranging from 20 to 60 months. Therapy is also variable, depending on the clinical stage of the disease. One of the mainly used therapeutical regimen is DAV or VAD-like (on the basis of the used drugs:
dexamethasone, adriamycin, vincristine), which gives a good response, without damaging healthy bone marrow cells that are necessary for transplantation.
A certain proportion of patients, however, is refractory to standard doses and undergoes side effects, even very serious. Interindividual variability in clinical response and in drug toxicity sensitivity, commonly observed with several chemotherapeutic protocols, can be associated to genetic defects, including SNPs, altering the levels of proteins implicated in the mechanism of action of the drug or in its biotransformation.
The relationship between response to chemotherapy and patient’s genotype can provide useful information that can be used to predict treatment efficacy and/or toxicity.
Aim of the present work is to evaluate individual response to DAV-therapy in patients affected by MM in relation to genetic polymorphism of two metabolic enzymes, Glutathione-S-Transferase-P1 (GSTP1 105Val) and NAD(P)H- Quinone:Oxido-reductase (NQO1 ProSer187), and of the transporter ABCB1
(C3435T). GSTP1 belongs to the family of Glutathione-S-Transferases that are phase II detoxification enzymes, catalysing GSH-conjugation of several xenobiotica and drugs. GSTP1 105Val is a variant with low thermal stability and
Abstract ________________________________________________________________________________________
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altered catalytic activity, as compared to wildtype allele. NQO1 encodes NAD(P)H-Quinone:Oxido-reductase, a cytosolic flavoenzyme involved in phase I drug metabolism and its variant 187 Ser is associated to complete loss of catalytic activity. MDR1 (or ABCB1) encoding a P-glycoprotein is a member of the ABC superfamily and is involved in active transport of several amphipathic molecules across cell membranes. Its main role is protecting the cell against drug toxicity, such as anthracyclins and vinca alkaloids. C3435T is the only variant that has been found associated to an altered expression of the protein in several tissues and is generally less expressed.
The group of patients recruited in different hospitals includes 115 MM patients, treated with DAV. Information about demographic (age and sex) and clinical variables (diagnose, treatment and follow-up) have been collected. Individual genotype has been analysed on DNA from blood cells with Taqman techniques.
Genotype analyses did not reveal any significant effect of NQO1 and MDR1 polymorphisms, in relation to therapy response, transplantation or overall survival at 30 months. On the contrary, GSTP1 105Val resulted significantly associated to a worse outcome following DAV therapy, but not to survival. This result indicates that GSTP1 could be a “predictive marker” of response to DAV in the management of Multiple Myeloma.
